Aging is associated with a loss of muscle mass in the form of sarcopenia and a loss of bone mass and density in the form of osteoporosis. Loss of muscle and bone mass with age are in turn underlying factors contributing to falls and fractures in the elderly, and these fractures are very costly both in terms of financial burden and quality of life. A critical barrier to progress in correcting the problem of muscle and bone loss with aging is a poor understanding of the molecular and cellular mechanisms underlying age-related musculoskeletal dysfunction. Our goal is to address this problem by providing critical, new information on the molecular and cellular mechanisms that control these processes, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Our central hypothesis is that extracellular vesicles (EVs), including exosomes and microvesicles, secreted by stem cells in bone marrow are significantly altered with aging, and that altered EVs contribute to muscle and bone loss by transporting specific microRNAs (miRNAs). This hypothesis is based on our preliminary data indicating that the miRNAs carried by EVs in bone marrow are significantly altered with age. Moreover, treatment of young bone marrow stromal cells (BMSCs) with EVs from bone marrow of aged animals suppresses the osteogenic differentiation of these cells, and treatment of young myoblasts with these EVs suppresses the expression of myogenic genes. Our preliminary results also suggest that these age-related changes in EV-derived miRNAs can be reversed with long-term caloric restriction. Our objectives are to 1) define how aging alters the secretion and cargo of EVs from bone-derived stem cells, and 2) determine how these EVs regulate key cellular events in bone loss and muscle atrophy.Our expected outcomes include 1) identification of EV-derived miRNAs that are actively secreted by bone marrow stem cells and are altered with age, and 2) determination of how these small molecules affect key cellular processes directly related to bone and muscle loss with aging. The impact of this project will be new findings on the role of EVs and miRNAs in the development of age-related diseases and end-organ injuries. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of age-induced pathologies. Aim 1 will test the hypothesis that bone- derived EVs, and their miRNAs, are induced by specific age-related stimuli.Aim 2 will test the hypothesis that EVs, and their miRNAs, altered with aging directly impact key cellular events in muscle atrophy and bone formation in vitro. Aim 3 will test the hypothesis that EVs, and their miRNAs, altered with aging directly impact key cellular events in muscle atrophy and bone formation in vivo.